Matrices formed of polymer and hydrophobic compounds for use in drug delivery

ABSTRACT

A lipid or other hydrophobic or amphiphilic compound (collectively referred to herein as “hydrophobic compounds”) is integrated into a polymeric matrix for drug delivery to alter drug release kinetics. In embodiments where the drug is water soluble, the drug is released over longer periods of time as compared to release from the polymeric matrix not incorporating the hydrophobic compound into the polymeric material. In contrast to methods in which a surfactant or lipid is added as an excipient, the hydrophobic compound is actually integrated into the polymeric matrix, thereby modifying the diffusion of water into the microparticle and diffusion of solubilized drug out of the matrix. The integrated hydrophobic compound also prolongs degradation of hydrolytically unstable polymers forming the matrix, further delaying release of encapsulated drug.

This application is a divisional of U.S. Ser. No. 09/255,179 now U.S.Pat. No. 6,423,34, filed Feb. 22, 1999 which claims priority to U.S.Ser. 60/083,636 filed Apr. 30, 1998 for “Lipid Polymer Compositions ForEnhanced Drug Delivery” by Howard Bernstein, Donald E. Chickering andJulie Ann Straub.

BACKGROUND OF THE INVENTION

The present invention is generally in the area of drug delivery, and isparticularly directed to polymer matrices containing drug and havinglipid or another hydrophobic or amphiphilic compound incorporatedtherein to modify the release kinetics. The matrices are preferably usedfor parenteral delivery. The matrices are preferably in the form ofmicroparticles.

Controlled or sustained release compositions have been developed overthe last twenty to thirty years in order to increase the amount of drugdelivered by any of a variety of routes, to sustain drug release in acontrolled fashion, thereby avoiding burst release which can causeelevated but transient drug levels, and to provide a means forcustomized release profiles. These formulations have taken many forms,including microparticles such as microspheres and microcapsules formedof drug and encapsulated or mixed with a natural or synthetic polymer,drug particles mixed with excipients such as surfactants to decreaseagglomeration of the particles, and devices such as the silasticcontrolled release depots which release drug as a function of diffusionof water into the device where it dissolves and releases drug back outthe same entry. It is difficult to achieve sustained release when thedelivery means consists solely of drug or drug and excipient since thedrug tends to solubilize relatively quickly. In contrast,non-biodegradable devices such as the silastic devices must be removedafter usage.

Microparticles have been formed using a wide range of techniques,including spray drying, hot melt, solvent evaporation, solventextraction, and mechanical means such as milling and rolling. Themicroparticles are typically formed of a biocompatible material havingdesirable release properties as well as being processible by techniquescompatible with the drug to be delivered. Many drugs are labile andcannot be encapsulated using harsh organic solvents or heat. Most ofthese methods result in formation of a structure where drug is releasedby diffusion of drug out of the microparticle and/or degradation of themicroparticle. In some cases it is desirable to further limit or controldiffusion.

It is an object of this invention to provide microparticles which haveincorporated therein means for limiting diffusion of drug out of themicroparticle.

It is a further object of this invention to provide biodegradablemicroparticles which have incorporated therein means for modifying thedegradation kinetics of the microparticles.

It is still another object of the present invention to providemicroparticles particularly well suited for parenteral drug delivery.

SUMMARY OF THE INVENTION

A lipid or other hydrophobic or amphiphilic compound (collectivelyreferred to herein as “hydrophobic compounds”) is integrated into apolymeric matrix for drug delivery to alter drug release kinetics. Inone embodiment where the drug is water soluble, the drug is releasedover longer periods of time as compared to release from the polymericmatrix not incorporating the hydrophobic compound into the polymericmaterial. In a further embodiment where the drug has low watersolubility, the drug is released over shorter periods of time ascompared to release from matrix not incorporating the hydrophobiccompound into the polymeric material. In contrast to methods in which asurfactant or lipid is added as an excipient, the hydrophobic compoundis actually integrated into the polymeric matrix, thereby modifying thediffusion of water into the microparticle and diffusion of solubilizeddrug out of the matrix. The integrated hydrophobic compound alsoprolongs degradation of hydrolytically unstable polymers forming thematrix, further delaying release of encapsulated drug.

The hydrophobic compound must be incorporated into the matrix and thematrix shaped using a technique which results in integration of thehydrophobic compound into the polymeric matrix, rather than at the outersurface of the matrix. In the preferred embodiment, the matrix is formedinto microparticles. The microparticles are manufactured with a diametersuitable for the intended route of administration. For example, with adiameter of between 0.5 and 8 microns for intravascular administration,a diameter of 1–100 microns for subcutaneous or intramuscularadministration, and a diameter of between 0.5 and 5 mm for oraladministration for delivery to the gastrointestinal tract or otherlumens. A preferred size for administration to the pulmonary system isan aerodynamic diameter of between one and three microns, with an actualdiameter of five microns or more. In the preferred embodiment, thepolymers are synthetic biodegradable polymers. Most preferred polymersare biocompatible hydrolytically unstable polymers like polyhydroxyacids such as polylactic acid-co-glycolic acid, polylactide,polyglycolide or polyactide co-glycolide, which may be conjugated topolyethylene glycol or other materials inhibiting uptake by thereticuloendothelial system (RES).

The hydrophobic compounds can be hydrophobic compounds such as somelipids, or amphiphilic compounds (which include both a hydrophilic andhydrophobic component or region). The most preferred amphiphiliccompounds are phospholipids, most preferablydipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine(DSPC), diarachidoylphosphatidylcholine (DAPC),dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine(DTPC), and dilignoceroylphatidylcholine (DLPC), incorporated at a ratioof between 0.01–60 (w/w polymer), most preferably between 0.1–30 (wlipid/w polymer).

Surface properties of the matrix can also be modified. For example,adhesion can be enhanced through the selection of bioadhesive polymers,which may be particularly desirable when the matrix is in the form ofmicroparticles administered to a mucosal surface such as in intranasal,pulmonary, vaginal, or oral administration. Targeting can also beachieved by selection of the polymer or incorporation within or couplingto the polymer to ligands which specifically bind to particular tissuetypes or cell surface molecules. Additionally, ligands may be attachedto the microparticles which effect the charge, lipophilicity orhydrophilicity of the particle.

DETAILED DESCRIPTION OF THE INVENTION

Methods are provided for the synthesis of polymeric delivery systemsconsisting of polymer matrices that contain an active agent, such as atherapeutic or prophylactic agent (referred to herein generally as“drug”). The matrices are useful in a variety of drug deliveryapplications, and can be administered by injection, aerosol or powder,orally, or topically. A preferred route of administration is via thepulmonary system or by injection. The incorporation of a hydrophobicand/or amphiphilic compound (referred to generally herein as“hydrophobic compound”) into the polymeric matrix modifies the period ofdrug release as compared with the same polymeric matrix without theincorporated hydrophobic compound, by altering the rate of diffusion ofwater into and out of the matrix and/or the rate of degradation of thematrix.

Reagents for Making Matrix Having Hydrophobic Compound IncorporatedTherein

As used herein, the term “matrix” refers to a structure including one ormore materials in which a drug is dispersed, entrapped, or encapsulated.The material can be crystalline, semi-crystalline, or amorphous. Thematrix can be in the form of pellets, tablets, slabs, rods, disks,hemispheres, or microparticles, or be of an undefined shape. As usedherein, the term microparticle includes microspheres and microcapsules,as well as microparticles, unless otherwise specified. Microparticlesmay or may not be spherical in shape. Microcapsules are defined asmicroparticles having an outer polymer shell surrounding a core ofanother material, in this case, the active agent. Microspheres aregenerally solid polymeric spheres, which can include a honeycombedstructure formed by pores through the polymer which are filled with theactive agent, as described below.

Polymers

The matrix can be formed of non-biodegradable or biodegradable matrices,although biodegradable matrices are preferred, particularly forparenteral administration. Non-erodible polymers may be used for oraladministration. In general, synthetic polymers are preferred due to morereproducible synthesis and degradation, although natural polymers may beused and have equivalent or even better properties, especially some ofthe natural biopolymers which degrade by hydrolysis, such aspolyhydroxybutyrate. The polymer is selected based on the time requiredfor in vivo stability, i.e. that time required for distribution to thesite where delivery is desired, and the time desired for delivery.

Representative synthetic polymers are: poly(hydroxy acids) such aspoly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolicacid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide),polyanhydrides, polyorthoesters, polyamides, polycarbonates,polyalkylenes such as polyethylene and polypropylene, polyalkyleneglycols such as poly(ethylene glycol), polyalkylene oxides such aspoly(ethylene oxide), polyalkylene terepthalates such as poly(ethyleneterephthalate), polyvinyl alcohols, polyvinyl ethers, polyvinyl esters,polyvinyl halides such as poly(vinyl chloride), polyvinylpyrrolidone,polysiloxanes, poly(vinyl alcohols), poly(vinyl acetate), polystyrene,polyurethanes and co-polymers thereof, derivativized celluloses such asalkyl cellulose, hydroxyalkyl celluloses, cellulose ethers, celluloseesters, nitro celluloses, methyl cellulose, ethyl cellulose,hydroxypropyl cellulose, hydroxy-propyl methyl cellulose, hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, celluloseacetate butyrate, cellulose acetate phthalate, carboxylethyl cellulose,cellulose triacetate, and cellulose sulphate sodium salt jointlyreferred to herein as “synthetic celluloses”), polymers of acrylic acid,methacrylic acid or copolymers or derivatives thereof including esters,poly(methyl methacrylate), poly(ethyl methacrylate),poly(butylmethacrylate), poly(isobutyl methacrylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecylacrylate) (jointly referred to herein as “polyacrylic acids”),poly(butyric acid), poly(valeric acid), andpoly(lactide-co-caprolactone), copolymers and blends thereof. As usedherein, “derivatives” include polymers having substitutions, additionsof chemical groups, for example, alkyl, alkylene, hydroxylations,oxidations, and other modifications routinely made by those skilled inthe art.

Examples of preferred biodegradable polymers include polymers of hydroxyacids such as lactic acid and glycolic acid, and copolymers with PEG,polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid),poly(valeric acid), poly(lactide-co-caprolactone), blends and copolymersthereof.

Examples of preferred natural polymers include proteins such as albuminand prolamines, for example, zein, and polysaccharides such as alginate,cellulose and polyhydroxyalkanoates, for example, polyhydroxybutyrate.The in vivo stability of the matrix can be adjusted during theproduction by using polymers such as polylactide co glycolidecopolymerized with polyethylene glycol (PEG). PEG if exposed on theexternal surface may elongate the time these materials circulate sinceit is hydrophilic.

Examples of preferred non-biodegradable polymers include ethylene vinylacetate, poly(meth)acrylic acid, polyamides, copolymers and mixturesthereof.

Bioadhesive polymers of particular interest for use in targeting ofmucosal surfaces, as in the gastrointestinal tract, includepolyanhydrides, polyacrylic acid, poly(methyl methacrylates), poly(ethylmethacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate),poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecylacrylate).

Solvents

A solvent for the polymer is selected based on its biocompatibility aswell as the solubility of the polymer and where appropriate, interactionwith the agent to be delivered. For example, the ease with which theagent is dissolved in the solvent and the lack of detrimental effects ofthe solvent on the agent to be delivered are factors to consider inselecting the solvent. Aqueous solvents can be used to make matricesformed of water soluble polymers. Organic solvents will typically beused to dissolve hydrophobic and some hydrophilic polymers. Preferredorganic solvents are volatile or have a relatively low boiling point orcan be removed under vacuum and which are acceptable for administrationto humans in trace amounts, such as methylene chloride. Other solvents,such as ethyl acetate, ethanol, methanol, dimethyl formamide (DMF),acetone, acetonitrile, tetrahydrofuran (THF), acetic acid, dimethylesulfoxide (DMSO) and chloroform, and combinations thereof, also may beutilized. Preferred solvents are those rated as class 3 residualsolvents by the Food and Drug Administration, as published in theFederal Register vol. 62, number 85, pp. 24301–24309 (May 1997).

In general, the polymer is dissolved in the solvent to form a polymersolution having a concentration of between 0.1 and 60% weight to volume(w/v), more preferably between 0.25 and 30%. The polymer solution isthen processed as described below to yield a polymer matrix havinghydrophobic components incorporated therein.

Hydrophobic and Amphiphilic Compounds

In general, compounds which are hydrophobic or amphiphilic (i.e.,including both a hydrophilic and a hydrophobic component or region) canbe used to modify penetration and/or uptake of water by the matrix,thereby modifying the rate of diffusion of drug out of the matrix, andin the case of hydrolytically unstable materials, alter degradation andthereby release of drug from the matrix.

Lipids which may be used include, but are not limited to, the followingclasses of lipids: fatty acids and derivatives, mono-, di andtriglycerides, phospholipids, sphingolipids, cholesterol and steroidderivatives, terpenes and vitamins. Fatty acids and derivatives thereofmay include, but are not limited to, saturated and unsaturated fattyacids, odd and even number fatty acids, cis and trans isomers, and fattyacid derivatives including alcohols, esters, anhydrides, hydroxy fattyacids and prostaglandins. Saturated and unsaturated fatty acids that maybe used include, but are not limited to, molecules that have between 12carbon atoms and 22 carbon atoms in either linear or branched form.Examples of saturated fatty acids that may be used include, but are notlimited to, lauric, myristic, palmitic, and stearic acids. Examples ofunsaturated fatty acids that may be used include, but are not limitedto, lauric, physeteric, myristoleic, palmitoleic, petroselinic, andoleic acids. Examples of branched fatty acids that may be used include,but are not limited to, isolauric, isomyristic, isopalmitic, andisostearic acids and isoprenoids. Fatty acid derivatives include12-(((7′-diethylaminocoumarin-3 yl)carbonyl)methylamino)-octadecanoicacid; N-[12-(((7′diethylaminocoumarin-3-yl)carbonyl)methyl-amino)octadecanoyl]-2-aminopalmitic acid, Nsuccinyl-dioleoylphosphatidylethanol amine and palmitoyl-homocysteine;and/or combinations thereof. Mono, di and triglycerides or derivativesthereof that may be used include, but are not limited to, molecules thathave fatty acids or mixtures of fatty acids between 6 and 24 carbonatoms, digalactosyldiglyceride, 1,2-dioleoyl-sn-glycerol;1,2-cdipalmitoyl-sn-3 succinylglycerol; and1,3-dipalmitoyl-2-succinylglycerol.

Phospholipids which may be used include, but are not limited to,phosphatidic acids, phosphatidyl cholines with both saturated andunsaturated lipids, phosphatidyl ethanolamines, phosphatidylglycerols,phosphatidylserines, phosphatidylinositols, lysophosphatidylderivatives, cardiolipin, and β-acyl-y-alkyl phospholipids. Examples ofphospholipids include, but are not limited to, phosphatidylcholines suchas dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine,dipentadecanoylphosphatidylcholine dilauroylphosphatidylcholine,dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine(DSPC), diarachidoylphosphatidylcholine (DAPC),dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine(DTPC), dilignoceroylphatidylcholine (DLPC); andphosphatidylethanolamines such as dioleoylphosphatidylethanolamine or1-hexadecyl-2-palmitoylglycerophosphoethanolamine. Syntheticphospholipids with asymmetric acyl chains (e.g., with one acyl chain of6 carbons and another acyl chain of 12 carbons) may also be used.

Sphingolipids which may be used include ceramides, sphingomyelins,cerebrosides, gangliosides, sulfatides and lysosulfatides. Examples ofSphinglolipids include, but are not limited to, the gangliosides GM1 andGM2.

Steroids which may be used include, but are not limited to, cholesterol,cholesterol sulfate, cholesterol hemisuccinate, 6-(5-cholesterol3β-yloxy)hexyl-6-amino-6-deoxy-1-thio-α-D-galactopyranoside,6-(5-cholesten-3β-tloxy)hexyl-6-amino-6-deoxyl-1-thio-α-Dmannopyranoside and cholesteryl)4′-trimethyl 35 ammonio)butanoate.

Additional lipid compounds which may be used include tocopherol andderivatives, and oils and derivatized oils such as stearlyamine.

A variety of cationic lipids such as DOTMA,N-[1-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium chloride; DOTAP,1,2-dioleoyloxy-3-(trimethylammonio)propane; and DOTB,1,2-dioleoyl-3-(4′-trimethyl-ammonio)butanoyl-sn glycerol may be used.

The most preferred lipids are phospholipids, preferably DPPC, DAPC,DSPC, DTPC, DBPC, DLPC and most preferably DPPC, DAPC and DBPC.

Other preferred hydrophobic compounds include amino acids such astryptophane, tyrosine, isoleucine, leucine, and valine, aromaticcompounds such as an alkyl paraben, for example, methyl paraben, andbenzoic acid.

The content of hydrophobic compound ranges from 0.01–60 (w hydrophobiccompound/w polymer); most preferably between 0.1–30 (w hydrophobiccompound/w polymer).

Targeting

Microparticles can be targeted specifically or non-specifically throughthe selection of the polymer forming the microparticle, the size of themicroparticle, and/or incorporation or attachment of a ligand to themicroparticles. For example, biologically active molecules, or moleculesaffecting the charge, lipophilicity or hydrophilicity of the particle,may be attached to the surface of the microparticle. Additionally,molecules may be attached to the microparticles which minimize tissueadhesion, or which facilitate specific targeting of the microparticlesin vivo. Representative targeting molecules include antibodies, lectins,and other molecules which are specifically bound by receptors on thesurfaces of cells of a particular type.

Inhibition of Uptake by the RES

Uptake and removal of the microparticles can be minimized through theselection of the polymer and/or incorporation or coupling of moleculeswhich minimize adhesion or uptake. For example, tissue adhesion by themicroparticle can be minimized by covalently binding poly(alkyleneglycol) moieties to the surface of the microparticle. The surfacepoly(alkylene glycol) moieties have a high affinity for water thatreduces protein adsorption onto the surface of the particle. Therecognition and uptake of the microparticle by the reticulo-endothelialsystem (RES) is therefore reduced.

In one method, the terminal hydroxyl group of the poly(alkylene glycol)is covalently attached to biologically active molecules, or moleculesaffecting the charge, lipophilicity or hydrophilicity of the particle,onto the surface of the microparticle. Methods available in the art canbe used to attach any of a wide range of ligands to the microparticlesto enhance the delivery properties, the stability or other properties ofthe microparticles in vivo.

Active Agents

Active agents which can be incorporated into the matrix for deliveryinclude therapeutic or prophylactic agents. These can be proteins orpeptides, sugars, oligosaccharides, nucleic acid molecules, or othersynthetic or natural agents. The agents may be labeled with a detectablelabel such as a fluorescent label or an enzymatic or chromatographicallydetectable agent.

Preferred drugs include antibiotics, antivirals, vaccines, vasodilators,vasoconstrictors, immunomodulatory compounds, including steroids,antihistamines, and cytokines such as interleukins, colony stimulatingfactors, tumor necrosis factor and interferon (α, β, γ),oligonucleotides including genes and antisense, nucleases,bronchodilators, hormones including reproductive hormones, calcitonin,insulin, erthropoietin, growth hormones, and other types of drugs suchas Antiban™.

Methods for Manufacture of Matrix

In the most preferred embodiment, microparticles are produced by spraydrying. Techniques which can be used to make other types of matrices, aswell as microparticles, include melt extrusion, compression molding,fluid bed drying, solvent extraction, hot melt encapsulation, andsolvent evaporation, as discussed below. A major criteria is that thehydrophobic compound must be dissolved or melted with the polymer ordispersed as a solid or a liquid in a solution of the polymer, prior toforming the matrix. As a result, the hydrophobic (or amphiphilic)compound is mixed throughout the matrix, in a relatively uniform manner,not just on the surface of the finished matrix. The active agent can beincorporated into the matrix as solid particles, as a liquid or liquiddroplets, or by dissolving the agent in the polymer solvent.

a. Solvent Evaporation. In this method the polymer and hydrophobiccompound are dissolved in a volatile organic solvent such as methylenechloride. A pore forming agent as a solid or as a liquid may be added tothe solution. The active agent can be added as either a solid or insolution to the polymer solution. The mixture is sonicated orhomogenized and the resulting dispersion or emulsion is added to anaqueous solution that may contain a surface active agent such as TWEEN™20, TWEEN™ 80, PEG or poly(vinyl alcohol) and homogenized to form anemulsion. The resulting emulsion is stirred until most of the organicsolvent evaporates, leaving microparticles. Several different polymerconcentrations can be used (0.05–0.60 g/ml). Microparticles withdifferent sizes (1–1000 microns) and morphologies can be obtained bythis method. This method is particularly useful for relatively stablepolymers like polyesters.

Solvent evaporation is described by E. Mathiowitz, et al., J. ScanningMicroscopy, 4, 329 (1990); L. R. Beck, et al., Fertil. Steril, 31, 545(1979); and S. Benita, et al., J. Pharm. Sci., 73, 1721 (1984), theteachings of which are incorporated herein.

Particularly hydrolytically unstable polymers, such as polyanhydrides,may degrade during the fabrication process due to the presence of water.For these polymers, the following two methods, which are performed incompletely organic solvents, are more useful.

b. Hot Melt Microencapsulation. In this method, the polymer and thehydrophobic compound are first melted and then mixed with the solid orliquid active agent. A pore forming agent as a solid or in solution maybe added to the solution. The mixture is suspended in a non-misciblesolvent (like silicon oil), and, while stirring continuously, heated to5° C. above the melting point of the polymer. Once the emulsion isstabilized, it is cooled until the polymer particles solidify. Theresulting microparticles are washed by decantation with a polymernon-solvent such as petroleum ether to give a free-flowing powder.Microparticles with sizes between one to 1000 microns can be obtainedwith this method. The external surfaces of particles prepared with thistechnique are usually smooth and dense. This procedure is used toprepare microparticles made of polyesters and polyanhydrides. However,this method is limited to polymers with molecular weights between1000–50,000.

Hot-melt microencapsulation is described by E. Mathiowitz, et al.,Reactive Polymers, 6, 275 (1987), the teachings of which areincorporated herein. Preferred polyanhydrides include polyanhydridesmade of bis-carboxyphenoxypropane and sebacic acid with molar ratio of20:80 (P(CPP-SA) 20:80) (Mw 20,000) and poly(fumaric-co-sebacic) (20:80)(MW 15,000) microparticles.

c. Solvent Removal. This technique was primarily designed forpolyanhydrides. In this method, the solid or liquid active agent isdispersed or dissolved in a solution of the selected polymer andhydrophobic compound in a volatile organic solvent like methylenechloride. This mixture is suspended by stirring in an organic oil (suchas silicon oil) to form an emulsion. Unlike solvent evaporation, thismethod can be used to make microparticles from polymers with highmelting points and different molecular weights. The external morphologyof particles produced with this technique is highly dependent on thetype of polymer used.

d. Spray Drying of Microparticles. Microparticles can be produced byspray drying by dissolving a biocompatible polymer and hydrophobiccompound in an appropriate solvent, dispersing a solid or liquid activeagent into the polymer solution, and then spray drying the polymersolution, to form microparticles. As defined herein, the process of“spray drying” a solution of a polymer and an active agent refers to aprocess wherein the solution is atomized to form a fine mist and driedby direct contact with hot carrier gases. Using spray drying apparatusavailable in the art, the polymer solution may be delivered through theinlet port of the spray drier, passed through a tube within the drierand then atomized through the outlet port. The temperature may be varieddepending on the gas or polymer used. The temperature of the inlet andoutlet ports can be controlled to produce the desired products.

The size of the particulates of polymer solution is a function of thenozzle used to spray the polymer solution, nozzle pressure, the flowrate, the polymer used, the polymer concentration, the type of solventand the temperature of spraying (both inlet and outlet temperature) andthe molecular weight. Generally, the higher the molecular weight, thelarger the particle size, assuming the concentration is the same.Typical process parameters for spray drying are as follows: polymerconcentration=0.005–0.20 g/ml, inlet temperature=20–1000° C., outlettemperature=10–300° C., polymer flow rate=5–2000 ml/min., and nozzlediameter=0.2–4 mm ID. Microparticles ranging in diameter between one andten microns can be obtained with a morphology which depends on theselection of polymer, concentration, molecular weight and spray flow.

If the active agent is a solid, the agent may be encapsulated as solidparticles which are added to the polymer solution prior to spraying, orthe agent can be dissolved in an aqueous solution which then isemulsified with the polymer solution prior to spraying, or the solid maybe cosolubilized together with the polymer in an appropriate solventprior to spraying.

e. Hydrogel Microparticles. Microparticles made of gel-type polymers,such as polyphosphazene or polymethylmethacrylate, are produced bydissolving the polymer in an aqueous solution, suspending if desired apore forming agent and suspending a hydrophobic compound in the mixture,homogenizing the mixture, and extruding the material through amicrodroplet forming device, producing microdroplets which fall into ahardening bath consisting of an oppositely charged ion orpolyelectrolyte solution, that is slowly stirred. The advantage of thesesystems is the ability to further modify the surface of themicroparticles by coating them with polycationic polymers, likepolylysine after fabrication. Microparticle particles are controlled byusing various size extruders.

Additives to Facilitate Matrix Formation

A variety of surfactants may be added to the continuous phase asemulsifiers if one is used during the production of the matrices.Exemplary emulsifiers or surfactants which may be used (0.1–5% byweight) include most physiologically acceptable emulsifiers. Examplesinclude natural and synthetic forms of bile salts or bile acids, bothconjugated with amino acids and unconjugated such as taurodeoxycholate,and cholic acid. In contrast to the methods described herein, thesesurfactant will coat the microparticle and will facilitate dispersionfor administration.

Pore Forming Agents

Pore forming agents can be included in an amount of between 0.01% and90% weight to volume, to increase matrix porosity and pore formationduring the production of the matrices. The pore forming agent can beadded as solid particles to the polymer solution or melted polymer oradded as an aqueous solution which is emulsified with the polymersolution or is co-dissolved in the polymer solution. For example, inspray drying, solvent evaporation, solvent removal, hot meltencapsulation, a pore forming agent such as a volatile salt, forexample, ammonium bicarbonate, ammonium acetate, ammonium chloride orammonium benzoate or other lyophilizable salt, is first dissolved inwater. The solution containing the pore forming agent is then emulsifiedwith the polymer solution to create droplets of the pore forming agentin the polymer. This emulsion is then spray dried or taken through asolvent evaporation/extraction process. After the polymer isprecipitated, the hardened microparticles can be frozen and lyophilizedto remove any pore forming agents not removed during themicroencapsulation process.

Methods for Administration of Drug Delivery Systems

The matrix can be administered orally, topically, to a mucosal surface(i.e., nasal, pulmonary, vaginal, rectal), or by implantation orinjection, depending on the form of the matrix and the agent to bedelivered. Useful pharmaceutically acceptable carriers include salinecontaining glycerol and TWEEN™ 20 and isotonic mannitol containingTWEEN™ 20. The matrix can also be in the form of powders, tablets, incapsules, or in a topical formulation such as an ointment, gel orlotion.

Microparticles can be administered as a powder, or formulated in tabletsor capsules, suspended in a solution or in a gel (ointment, lotion,hydrogel). As noted above, the size of the microparticles is determinedby the method of administration. In the preferred embodiment, themicroparticles are manufactured with a diameter of between 0.5 and 8microns for intravascular administration, a diameter of 1–100 micronsfor subcutaneous or intramuscular administration, and a diameter ofbetween 0.5 and 5 mm for oral administration for delivery to thegastrointestinal tract or other lumens, or application to other mucosalsurfaces (rectal, vaginal, oral, nasal). A preferred size foradministration to the pulmonary system is an aerodynamic diameter ofbetween one and three microns, with an actual diameter of five micronsor more, as described in U.S. Pat. No. 5,855,913, which issued on Jan.5, 1999, to Edwards, et al. Particle size analysis can be performed on aCoulter counter, by light microscopy, scanning electron microscopy, ortransmittance electron microscopy.

In the preferred embodiment, microparticles are combined with apharmaceutically acceptable carrier such as phosphate buffered saline orsaline or mannitol, then an effective amount administered to a patientusing an appropriate route, typically by injection into a blood vessel(i.v.), subcutaneously, intramuscularly (IM) or orally. Microparticlescontaining an active agent may be used for delivery to the vascularsystem, as well as delivery to the liver and renal systems, incardiology applications, and in treating tumor masses and tissues. Foradministration to the pulmonary system, the microparticles can becombined with pharmaceutically acceptable bulking agents andadministered as a dry powder. Pharmaceutically acceptable bulking agentsinclude sugars such as mannitol, sucrose, lactose, fructose andtrehalose. The microparticles also can be linked with ligands thatminimize tissue adhesion or that target the microparticles to specificregions of the body in vivo as described above.

The methods and compositions described above will be further understoodwith reference to the following non-limiting examples.

EXAMPLE 1 Preparation of PLGA:DAPC Drug Delivery Particles

30 grams of PLGA (50:50) (IV 0.4 dL/g Boehringer Ingelheim), 1.8 g ofdiarachidoylphosphatidylcholine (Avanti, Birmingham, Ala.) and 495 mg ofAzure A (Sigma Chemicals, St. Louis, Mo.) were dissolved in 1000 ml ofmethylene chloride. The solution was pumped at a flowrate of 20 mL/minand spray dried using a Bucchi Lab spray dryer. The inlet airtemperature was 40° C. The dried microparticle powder was collected andstored at −20° C. until analysis. Size of the microparticles wasperformed using a Coulter multisizer II. The microparticles have avolume average mean diameter of 5.982 microns.

18 grams of PLGA (50:50) (IV 0.4 dL/g Boehringer Ingelheim) and 1.08 gof diarachidoylphosphatidylcholine (Avanti, Birmingham, Ala.) weredissolved in 600 mL of methylene chloride. 38.9 mg of Eosin Y (SigmaChemicals) was dissolved in 38.9 mL of a 0.18 g/ml ammonium bicarbonatesolution. The eosin solution was emulsified with the polymer solutionusing a Silverson homogenizer at 7000 rpm for 8 minutes. The solutionwas pumped at a flowrate of 20 mL/min and spray dried using a Bucchi Labspray dryer. The inlet air temperature was 40° C. The driedmicroparticle powder was collected and stored at −20° C. until analysis.Size analysis of the microparticles was performed using a Coultermultisizer II. The microparticles have a volume average mean diameter of6.119 microns.

Modifications and variations of the present invention will be obvious tothose skilled in the art from the foregoing detailed description and areintended to come within the scope of the following claims.

1. A therapeutic agent delivery system comprising a matrix, wherein thematrix comprises a biodegradable polymer having incorporated therein thetherapeutic agent and an amphiphilic or hydrophobic compoundincorporated within the matrix in an effective amount to modify thediffusion of water into the matrix and the release of the therapeuticagent from the matrix, wherein therapeutic agent is released overshorter periods of time as compared to release from a matrix notincorporating the hydrophobic or amphiphilic compound, wherein thetherapeutic agent is selected from the group consisting of proteins,peptides, antibiotics, antivirals, steroids, antihistamines,bronchodilators, and hormones, wherein the hydrophobic or amphiphiliccompound is selected from the group consisting of fatty acids andderivatives thereof, mono-, di and triglycerides, phospholipids, aminoacids, and aromatic compounds, and wherein the matrix is formed byemulsifying a polymer solution, the therapeutic agent and a volatilesalt and then removing the volatile salt and solvent.
 2. The system ofclaim 1, wherein the volatile salt is selected from the group consistingof ammonium bicarbonate, ammonium acetate and ammonium chloride.
 3. Thesystem of claim 1, wherein the polymer is selected from the groupconsisting of poly(hydroxy acids), polyanhydrides, polyorthoesters,polyurethanes, and blends and copolymers thereof.
 4. The system of claim3, wherein the polymer is selected from the group consisting ofpoly(lactide), poly(glycolide), poly(lactide-co-gylcolide), poly(butyricacid), poly(valeric acid), copolymers of hydroxy acids with polyethyleneglycol (PEG), poly(lactide-co-caprolactone).
 5. The system of claim 1,further comprising a pharmaceutically acceptable carrier.
 6. The systemof claim 5 in a form selected from the group consisting of powders,tablets, capsules, ointments, gels, lotions, or suspensions.